Diabetes is characterized by impaired glucose metabolism, and manifests itself, among other ways, by elevated blood glucose (BG) levels in untreated diabetic patients. Diabetes is generally known as being one of two types: type 1 diabetes (or insulin-dependent diabetes mellitus), which arises when patients lack insulin-producing β cells in their pancreatic glands; and type 2 diabetes (or non-insulin dependent diabetes mellitus), which arises when patients have impaired β-cell function, in addition to a range of other abnormalities.
Treatment of type 2 diabetes can include the administration of common agents that stimulate β-cell function or that enhance the tissue sensitivity of patients towards insulin. Various agents are known to stimulate β-cell function, including, for example, sulfonylureas, such as tolbutamide, glibenclamide, glipizide, chlorpropamide, and gliclazide, and repaglinide. Other agents are known to enhance tissue sensitivity towards insulin, such as metformin.
Although such common agents are widely used in the treatment of type 2 diabetes, the therapy is often leads to unsatisfactory results. In many patients, such treatments do not normalize BG levels to the desired degree, which places patients at a higher risk of acquiring further diabetic complications. Furthermore, these treatments are known to cause adverse effects in many patients. For example, the sulfonylureas may induce hypoglycemia when taken alone or in combination with other drugs. And while metformin does not induce hypoglycemia to the same degree as sulfonylureas, it has other adverse effects. For example, metformin may cause gastrointestinal distress, where the incidence of such distress may increase with higher doses. Long-term use of metformin can also cause increased homocysteine levels and can lead to malabsorption of vitamin B12. Metformin may also induce production of lactate, which can contribute to lactic acidosis in some patient populations.
In recent years, metformin has been approved for use in combination with other antidiabetic drugs. For example, metformin has been combined with certain sulfonylureas, including glipizide and glibenclamide. Metformin has also been combined with agents that stimulate PPAR-γ receptors, such as pioglitazone and rosiglitazone, and with agents that stimulate the release of insulin from the pancreas, such as repaglinide.
But in any combination therapy, metformin can still exhibit adverse effects, including those described above. Therefore, there is a need to discover agents that, when used with metformin, may exhibit a synergistic effect on glycemic control, thereby allowing a subjects to reduce their daily intake of metformin.
Glucokinase (GK) is an enzyme that, among other things, facilitates phosphorylation of glucose to glucose-6-phosphate. In vertebrates, GK-mediated glucose phosphorylation typically occurs in cells in the liver, pancreas, gut, and brain. In each of these organs, GK can play a role in regulating carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising and/or falling levels of BG.
Small-molecule GK activators are useful in treating type 2 diabetes because they can activate GK, and thereby indirectly reduce the body's demand for insulin. WO 2005/066145 describes novel compounds that are useful as GK activators, and are therefore useful, among other things, for the treatment of type 2 diabetes. Among the disclosed compounds are {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and pharmaceutically acceptable salts thereof (referred to collectively as “Urea Derivatives 1” or “UD1”). The free acid, {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid, is referred to herein as “UD1-FA”.